tbuckley/cabot-search huggingface dataset:
OTHR-08. Pediatric Neurologic Assessment in Neuro-oncology (pNANO) Scale: A tool to assess neurologic function for Response Assessment in Neuro-oncology (RAPNO)
Authors: Fatema Malbari, Craig Erker, Pablo Hernáiz Driever, Natasha Pillay-Smiley, Robert A Avery, Robert Craig Castellino, Antoinette A Y N Schouten-van Meeteren, Alicia C Lenzen, Rick Brandsma, Kim Kramer, Patricia A Baxter, Girish Dhall, Stewart Goldman, Patrick Y Wen, Michael Prados, Roger J Packer, Katherine E Warren, Lakshmi Nayak
Journal: Neuro-Oncology (2022)

Abstract Background: The Neurologic Assessment in Neuro-Oncology (NANO) scale, a standardized metric to objectively measure neurologic function in adult brain tumor patients, complements radiographic assessment in evaluating outcomes of neuro-oncology patients in clinical trials and clinical practice. Currently, there is no standardized measure for neurologic function in pediatric neuro-oncology patients despite their distinct clinical presentations and tumor locations. Therefore, we developed a dedicated pediatric NANO (pNANO) scale. Methods: An international group of pediatric neurologists and adult and pediatric neuro-oncologists convened bi-weekly over 5 months to draft the pNANO scale as an objective and quantifiable measure of neurologic function in children that can be administered during routine examination by pediatric-trained providers of any sub-specialty and be utilized together with other indicators to assess response in clinical trials. Results: Ten relevant domains of neurologic function were identified based on common pediatric brain tumor locations: gait, strength, cerebellar function, visual fields, visual acuity, facial strength, level of consciousness, extraocular movements, dysarthria and dysphagia. For each domain, developmental age appropriate levels of function were defined and categorized. Each domain, based on direct observation and testing during any routine neurological exam, can be used for longitudinal monitoring. Conclusions: The pNANO scale has been developed and aims to provide an objective metric of neurologic function for pediatric brain tumor patients. This scale will be tested for reliability, feasibility and inter-observer variability. Consistent evaluation of neurologic function using pNANO along with radiographic assessment will enable more comprehensive and standardized response assessment in pediatric neuro-oncology patients enrolled in clinical trials.
Deciphering genomic characteristics of <i>ERBB</i> family members potentially involved in the recovery of anti-cancer immunity for intrahepatic cholangiocarcinoma patients.
Authors: Wei Zhang, Zanmei Xu, Zewu Zhang, Tianqiang Song, Fei Pang
Journal: Journal of Clinical Oncology (2022)

e16003 Background: Previous studies showed that the efficacy of immune checkpoint inhibitor (ICI) is enhanced in hepatobiliary cancers harboring activating gene alterations of ERBB family members. The purpose of this study was to explore genomic characteristics of ERBB family members as well as the relationship of them with the activity of anti-cancer immunity in Chinese intrahepatic cholangiocarcinoma (ICC) patients. Methods: Fifty-four ICC patients which carried at least one gene mutation of ERBB family members were pre-selected from 508 ICC patients included in the China Pan-cancer project of OrigiMed 2020 (https://www.cbioportal.org/study/summary?id=pan_origimed_2020). Targeted sequencing was implemented with cancer-related 450-gene panel. Tumor mutation burden (TMB) and microsatellite status were evaluated. To explore the molecular mechanisms, two human cholangiocarcinoma cell lines, RBE and HuCCT1, were transfected with a lentivirus to obtain the cells with stable S310F mutation and overexpression of ERBB2. Results: The variation frequencies of EGFR, ERBB2, ERBB3 and ERBB4 were 2.8% (14/508), 3.5% (18/508), 3.3% (17/508) and 2.4% (12/508) in Chinese ICC patients, respectively. All the patients harboring ERBB family gene mutations were classified as TMB-H (cutoff = 10 Muts/Mb), when co-mutated with ACVR2A or TGFBR2. Moreover, ACVR2A and TGFBR2 were identified as driver genes in the cohort with oncodriveCLUST. TMB and the proportion of MSI-H patients were significantly elevated when ERBB family members co-mutated with ACVR2A (mutation vs wild: TMB, 38.2 ± 19.1 vs 7.0 ± 8.6 Muts/Mb, p&lt;0.0001; MSI-H, 77.8% vs 4.9%, p&lt;0.0001), or with TGFBR2 (TMB, 33.1 ± 8.7 vs 9.0 ± 14.4 Muts/Mb, p&lt;0.0001; MSI-H, 83.3% vs 9.1%, p&lt;0.001). Besides, ACVR2A and TGFBR2 were enriched in TGF-β pathway. Flow cytometry analysis revealed that ERBB2 S310F mutation and amplification were increased by approximate 3-fold and 3.5-fold in PD-L1 expression of cell line RBE ( p &lt; 0.0001, respectively); by approximate 2-fold and 3-fold upregulation of PD-L1 expression in cell line HUCCT1 ( p &lt; 0.0001, respectively). Western-blot results suggested that ERBB2 mutation/overexpression mediated PD-L1 upregulation through the RAS/ERK/c-JUN pathway. T cell cytotoxicity-mediated killing assay demonstrated that ERBB2 S310F mutation and overexpression induced the recovery of anti-cancer immunity by about 30% ( p &lt; 0.05) both in RBE and HuCCT1 cells. Conclusions: The present study revealed two distinct genomic characteristics potentially involved in the recovery of anti-cancer immunity of intrahepatic cholangiocarcinoma patients: on one hand, co-mutation of ERBB family genes with ACVR2A or TGFBR2 was enriched in TGF-β pathway, contributing to MSI-H/TMB-H; on the other hand, ERBB2 might impact expression of PD-L1 by regulating the RAS/ERK/c-Jun pathways.
Risk factors for cardiovascular events in patients treated with immunotherapy.
Authors: Yago Garitaonaindia, Mariola Blanco, Fernando Franco, Maria Torrente, Virginia Calvo, Ana Collazo, Aranzazu Gonzalez del Alba, Juan Cristobal Sanchez, Lourdes Gutiérrez, Ana Royuela, Beatriz Nuñez Garcia, Miriam Mendez, Roberto Hernández, Blanca Cantos Sanchez de Ibarguen, Marta Martinez Cutillas, Cristina Traseira, Ramon Aguado, Guillermo Visedo Ceballos, Mariano Provencio
Journal: Journal of Clinical Oncology (2022)

e18736 Background: Immunotherapy (IO) is increasingly widespread in current clinical practice; however, little is known about its cardiovascular safety profile. The aim of this study is to identify clinical factors that are associated with increased risk of having a cardiac event (CE). Methods: we conducted a retrospective study in a single institution including patients treated with IO from 2014 to 2020. We analyzed their clinical characteristics and the CE developed during IO treatment and compared those who had a registered CE with those who had not. Results: 378 patients were analyzed. After a mean-follow up 15.9 months, we registered the following CE: ECG abnormalities 12.2%, congestive heart failure 3.4%, pulmonary embolism 1.9%, coronary syndrome 0.8%, myocarditis 0.5% and pericarditis 0.5%. The specific cardiac mortality was 0.8%. Results are shown in Table. Conclusions: In our study, elder age, history of ischemic heart disease or arrythmia, and reporting other immune-related adverse events (irAE), appear to be risk factors for developing a CE during IO treatment. Although most are well-known cardiovascular risk factors, the relationship between other irAEs and CE should be highlighted, and prospective studies are needed to delve into this hypothesis.[Table: see text]
Utility of CT rendering and Radiomic Features analysis in post-chemotherapy retroperitoneal lymph node dissection
Authors: A. Scavuzzo, P. Figueroa Rodriguez, N. Jimenez Guedulain, A. Hernandez Mendez, S. Muruato Araiza, J.D.J. Cendejas Gomez, A. Quiroz Compeán, O.D. Victorio Vargas, M.A. Jimenez Rios
Journal: European Urology (2022)
Predictive value of cystatin c in methotrexate elimination in patients with osteosarcoma.
Authors: Zengjun Liu, Yonggang Wang, Jing Xu, Wenyu Hu, Changsheng Yang, Dongyuan Zhu, Lei Zhou, Mengyao Liu, Hongtao Li
Journal: Journal of Clinical Oncology (2022)

e23522 Background: High-dose methotrexate (HDMTX) is a renally eliminated and nephrotoxic therapy for osteosarcoma (OS). Serum cystatin C (Cys C) has emerged as an alternative to serum creatinine (Scr) for estimation of glomerular filtration rate (GFR). We aim to analyze the value of the baseline Cys C in predicting MTX elimination in patients with OS. Methods: All consecutive patients who were treated with HDMTX in Shanghai Jiao Tong University Affiliated Sixth People¡¯s Hospital, between November 2011 and April 2018, were retrospectively reviewed. The baseline GFR was calculated by three different equations based on the Scr, Cys C and their combination. MTX concentrations at 24, 48 and 72 hours after the termination of infusion were routinely monitored using high performance liquid chromatography. Results: A total of 158 courses of MTX infusion were administered. The incidences of delayed excretion of MTX at 24, 48, and 72 hours (serum concentrations at 24 h &gt; 10 μmol/L, 48h &gt; 1 μmol/L, 72h &gt;0.1 μmol/L) were 62.3%, 44.9% and 29.7%, respectively. The baseline Scr in the delayed excretion (DE) group were significantly lower than that in the normal excretion (NE) group at all three time points (24h: 58.8 µmol/L vs 47.86 µmol/L, P£¼0.05; 48h: 59.02 µmol/L vs 47.48 µmol/L, P£¼0.05; 72h: 62.29 µmol/L vs 51.51 µmol/L, P£¼0.05). However, the baseline Cys C in the DE group were similar to that in the NE group at all three time points (24h: 0.96 mg/L vs 0.90 mg/L, P = 0.11; 48h: 0.96 mg/L vs 0.92 mg/L, P = 0.17; 72h: 0.96 mg/L vs 0.93 mg/L, P£¾0.05). The Scr-based estimated GFR in the DE group were significantly lower than that in the NE group at all three time points (24h: 148.42 mL/min vs 186.79 mL/min, P£¼0.05; 48h: 147.24 mL/min vs 188.82 mL/min, P£¼0.05; 72h: 142.95 mL/min vs 171.04 mL/min, P£¼0.05). The Scr- and Cys C-based estimated GFR in the DE group were also significantly lower than that in the NE group at all three time points (24h: 140.33 mL/min vs 161.39 mL/min, P£¼0.05; 48h: 141.69 mL/min vs 159.04 mL/min, P£¼0.05; 72h: 138.33 mL/min vs 152.31 mL/min, P£¼0.05). However, the Cys C based estimated GFR in the DE group were similar to that in the NE group at all three time points (24h: 95.95 mL/min vs 101.31 mL/min, P = 0.183; 48h: 97.49 mL/min vs 98.64 mL/min, P = 0.763; 72h: 95.30 mL/min vs 99.06 mL/min, P = 0.375). Conclusions: Baseline Cys C alone is unable to predict MTX elimination in patients with OS.[Table: see text]
Molecular imaging approaches to facilitate bacteria-mediated cancer therapy
Authors: Su Woong Yoo, Seong Young Kwon, Sae-Ryung Kang, Jung-Joon Min
Journal: Advanced Drug Delivery Reviews (2022)

Bacteria-mediated cancer therapy is a potential therapeutic strategy for cancer that has unique properties, including broad tumor-targeting ability, various administration routes, the flexibility of delivery, and facilitating the host's immune responses. The molecular imaging of bacteria-mediated cancer therapy allows the therapeutically injected bacteria to be visualized and confirms the accurate delivery of the therapeutic bacteria to the target lesion. Several hurdles make bacteria-specific imaging challenging, including the need to discriminate therapeutic bacterial infection from inflammation or other pathologic lesions. To realize the full potential of bacteria-specific imaging, it is necessary to develop bacteria-specific targets that can be associated with an imaging assay. This review describes the current status of bacterial imaging techniques together with the advantages and disadvantages of several imaging modalities. Also, we describe potential targets for bacterial-specific imaging and related applications.
Noninvasive proteomic biomarkers for alcohol-related liver disease
Authors: Lili Niu, Maja Thiele, Philipp E. Geyer, Ditlev Nytoft Rasmussen, Henry Emanuel Webel, Alberto Santos, Rajat Gupta, Florian Meier, Maximilian Strauss, Maria Kjaergaard, Katrine Lindvig, Suganya Jacobsen, Simon Rasmussen, Torben Hansen, Aleksander Krag, Matthias Mann
Journal: Nature Medicine (2022)

Abstract Alcohol-related liver disease (ALD) is a major cause of liver-related death worldwide, yet understanding of the three key pathological features of the disease—fibrosis, inflammation and steatosis—remains incomplete. Here, we present a paired liver–plasma proteomics approach to infer molecular pathophysiology and to explore the diagnostic and prognostic capability of plasma proteomics in 596 individuals (137 controls and 459 individuals with ALD), 360 of whom had biopsy-based histological assessment. We analyzed all plasma samples and 79 liver biopsies using a mass spectrometry (MS)-based proteomics workflow with short gradient times and an enhanced, data-independent acquisition scheme in only 3 weeks of measurement time. In plasma and liver biopsy tissues, metabolic functions were downregulated whereas fibrosis-associated signaling and immune responses were upregulated. Machine learning models identified proteomics biomarker panels that detected significant fibrosis (receiver operating characteristic–area under the curve (ROC–AUC), 0.92, accuracy, 0.82) and mild inflammation (ROC–AUC, 0.87, accuracy, 0.79) more accurately than existing clinical assays (DeLong’s test, P &lt; 0.05). These biomarker panels were found to be accurate in prediction of future liver-related events and all-cause mortality, with a Harrell’s C -index of 0.90 and 0.79, respectively. An independent validation cohort reproduced the diagnostic model performance, laying the foundation for routine MS-based liver disease testing.
NT-seq: a chemical-based sequencing method for genomic methylome profiling
Authors: Xuwen Li, Shiyuan Guo, Yan Cui, Zijian Zhang, Xinlong Luo, Margarita T. Angelova, Laura F. Landweber, Yinsheng Wang, Tao P. Wu
Journal: Genome biology (2022)

Abstract DNA methylation plays vital roles in both prokaryotes and eukaryotes. There are three forms of DNA methylation in prokaryotes: N 6 -methyladenine (6mA), N 4 -methylcytosine (4mC), and 5-methylcytosine (5mC). Although many sequencing methods have been developed to sequence specific types of methylation, few technologies can be used for efficiently mapping multiple types of methylation. Here, we present NT-seq for mapping all three types of methylation simultaneously. NT-seq reliably detects all known methylation motifs in two bacterial genomes and can be used for identifying de novo methylation motifs. NT-seq provides a simple and efficient solution for detecting multiple types of DNA methylation.
Comprehensive whole-exome and transcriptome profiling to identify actionable alterations associated with response to PARP inhibitors in breast cancer.
Authors: Susan M. Dombrowski, Sameer S. Udhane, Gargi D. Basu, David W. Hall, Jess W. Hoag, Fadel S. Alyaqoub, Pawan Noel, Szabolcs Szelinger, Min Wang, Audrey A. Ozols, Janine R. LoBello, Snehal Govind Thakkar, Frederick L. Baehner, Joyce O'Shaughnessy
Journal: Journal of Clinical Oncology (2022)

1096 Background: The use of targeted therapies identified using genetic and genomic approaches is now routine in breast cancer (BC). In this clinical lab experience study the frequency of actionable somatic alterations in DNA repair pathway genes associated with the use of PARP inhibitors (PARPi) is described. Methods: BC samples were sequenced with the Oncomap ExTra assay, which uses whole-exome DNA sequencing with germline subtraction to detect somatic single base substitutions, indels, and copy number alterations, and RNA sequencing to detect gene fusions. Clinically actionable alterations were defined as associated with FDA approved drugs or clinical trial enrollment. Here, the focus is on 49 repair genes associated with PARPi response: ARID1A, ATM, ATR, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CDK12, CHEK1/2, EPCAM, ERCC1/2/3/4/5, FANCA/C/D2/E/F/G/I/L/M, MLH1, MRE11A, MSH2/6, MUTYH, NBN, PALB2, PMS2, PPP2R2A, PTEN, RAD21/50/51/51B/51C/51D/52/54L, XRCC1/2/3. Results: Of 1103 BCs, 246 (22.3%) had mutations in repair genes; 69 (6.3%) were in BRCA1/2. Repair gene mutations were less common in HER2 + cancers (n=27, 14.3%) compared to HR + HER2 - (n=156, 23.9%) or TN cancers (n=49, 26.1%) (p&lt;0.01). Across subtypes, the top four most commonly mutated of the repair genes were PTEN (27.2%), ARID1A (22.8%), BRCA2 (14.2%), and BRCA1 (14.2%); 33 cancers (13.4%) had mutations in multiple (≥2) repair genes. For the 69 cancers with BRCA1/2 mutations, 11 (15.9%) carried other repair gene mutations (9 of 35 BRCA1; 3 of 35 BRCA2). RNA sequencing found 19 fusions in repair genes in 17 patients (1.5%); CDK12 was involved in 13 (68.4%), and RAD51C in 3 (15.8%). Fusion incidence was more frequent in HER2 + cancers (p&lt;0.01) (Table). Conclusions: PARPi therapy is FDA approved for HER2 - germline BRCA1/2 mutated BC patients. Recent evidence suggests somatic BRCA1/2 mutations predict PARPi benefit (Tung, NM. J Clin Oncol 2020). In addition to BRCA1/2 alterations, our study also highlights the importance of alterations in other DNA repair genes associated with response to PARPi. Trials are ongoing to determine if these genes predict for PARPi benefit.[Table: see text]
ICI in combination with chemotherapy or anti-angiogenic agents as second-line or beyond treatment for advanced non-small cell lung cancer: A retrospective study.
Authors: Lin Wu, bolin chen, Jingyi Wang, Xingxiang Pu, Jia Li, Qianzhi Wang, Liyu Liu, Yan Xu, Li Xu, Yi Kong, Kang Li, Fang Xu, Shuzhi Liang
Journal: Journal of Clinical Oncology (2022)

e21057 Background: Immune checkpoint inhibitors (ICIs), which are currently used in the standard second-line treatment for non-small cell lung cancer (NSCLC), have largely improved the prognosis of advanced NSCLC. However, patients treated with ICI monotherapy have low response rates; hence, there is an urgent need to expand the population responding to immunotherapy treatment. This study aimed to explore the efficacy and safety of the combination of ICI with chemotherapy or anti-angiogenic therapy compared to ICI monotherapy in patients previously treated for advanced NSCLC. Methods: Data was collected from previously treated patients with NSCLC who further received ICI monotherapy or combination therapy. The distribution of clinical variables was assessed using the chi-square test or Fisher's exact test. The relationship between descriptive variables and survival was described using Kaplan–Meier curves and compared by log-rank test. Cox proportional-hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to confirm survival differences. Results: A total of 145 patients were included in this study, of which 63 were in the ICI monotherapy group, 57 were in the ICI with chemotherapy group, and 25 were in the ICI with anti-angiogenic therapy group. Compared with the ICI monotherapy group, the ICI with chemotherapy group had significantly higher ORR (31.6% vs. 11.1%, P = 0.006), DCR (84.2% vs. 61.9%, P= 0.006), PFS (mPFS: 6.37 vs. 3.47 months, P&lt; 0.0001; HR = 0.42, 95% CI: 0.29–0.63, P&lt; 0.0001), and OS (mOS: 18.60 vs. 8.47 months, P&lt; 0.0001; HR = 0.40, 95% CI: 0.25–0.64, P= 0.0001). In addition, the ICI with anti-angiogenic therapy group also had significantly elevated DCR (88% vs. 61.9%, P= 0.02), PFS (mPFS: 8.17 vs. 3.47 months, P&lt; 0.0001; HR = 0.30, 95% CI: 0.17–0.53, P&lt; 0.0001), and OS (mOS: 19.20 vs. 8.47 months, P= 0.006; HR = 0.44, 95% CI: 0.24–0.80, P= 0.007) compared with the ICI monotherapy group. There was no significant difference between the ICI with chemotherapy group and the ICI with anti-angiogenic therapy group. Meanwhile, the addition of chemotherapy or anti-angiogenics did not increase immune-related adverse events and had a good safety profile. Conclusions: For previously treated patients with advanced NSCLC, treatment with ICI in combination with chemotherapy led to enhanced ORR, DCR, PFS, and OS compared to treatment with ICI monotherapy. Moreover, treatment with ICI combined with anti-angiogenic therapy led to enhanced DCR, PFS, and OS compared to treatment with ICI monotherapy. The combination of immunotherapies is a promising second-line treatment option for some of the patients in this study, and the findings of this study necessitate the need for further exploration.
Associations of a breast cancer polygenic risk score with tumor characteristics and survival.
Authors: Josephine Lopes Cardozo, Irene L. Andrulis, Devilee Peter, Thilo Dörk, Caroline Drukker, Peter A. Fasching, Maartje J. Hooning, Renske Keeman, Heli Nevanlinna, Emiel J. Rutgers, Laura van 't Veer, Per Hall, Stig Egil Bojesen, Easton Douglas, Diana Eccles, Paul Pharoah, Marjanka Schmidt
Journal: Journal of Clinical Oncology (2022)

563 Background: A polygenic risk score (PRS) consisting of 313 single nucleotide polymorphisms (PRS 313 ) is associated with risk of breast cancer and contralateral breast cancer. One of the most promising clinical applications for the use of PRS is to provide a personalized risk assessment to individualize breast cancer screening programs. This study aimed to evaluate the association of the PRS 313 with clinical-pathological characteristics and survival of breast cancer. Methods: Women of European ancestry with invasive breast cancer were included, 98,397 women from the Breast Cancer Association Consortium (BCAC) and 683 women from the MINDACT trial. Associations between PRS 313 (continuous, per SD) and clinical-pathological characteristics, including the 70-gene signature for patients included in MINDACT, were evaluated with logistic regression analyses. Associations of PRS 313 with overall survival (OS), breast cancer-specific survival (BCSS) and distant metastasis-free interval (DMFI) were evaluated with Cox regression analyses, adjusted for clinical-pathological characteristics and treatment. Results: The PRS 313 was associated with favorable tumor characteristics. In BCAC, increasing PRS 313 was mostly associated with lower grade, hormone receptor-positive tumors, and with smaller tumor size. In MINDACT, PRS 313 was associated with a low risk 70-gene signature, but the association was attenuated after adjustment for clinical-pathological characteristics. In BCAC, univariable analyses showed an association of PRS 313 with better survival, hazard ratio (HR) per unit SD increase of PRS 313 for OS: 0.96 (95% confidence interval (CI): 0.94-0.97), for BCSS HR: 0.96 (95% CI: 0.94-0.98) and for DMFI HR: 0.98 (95% CI: 0.96-1.00). The association in the unadjusted analysis was explained by differences in clinical-pathological characteristics (and treatment) and disappeared after adjustment: OS HR: 1.01 (95% CI: 0.98-1.05), BCSS HR: 1.02 (95% CI: 0.98-1.07) and DMFI HR: 1.03 (95% CI: 0.99-1.07). Conclusions: An increased PRS 313 is associated with favorable tumor characteristics but was not independently associated with prognosis. This information is crucial input for modelling effective stratified screening programs, especially in the current era of optimized (systemic) treatments. Given the significant increase in breast cancer risk associated with increasing PRS 313 , absolute breast cancer mortality will still be higher for women with higher PRS 313 .